Idiopathic hypogonadotropic hypogonadism (IHH) is due to a deficiency of GnRH. The major goal of this proposal is to isolate the gene(s) important in the genesis of IHH. In the hypogonadal mouse, hypogonadotropic hypogonadism is due to a GnRH gene deletion, but no GnRH gene mutations have been identified in humans with IHH. Except for two X-linked disorders, Kallmann's syndrome, consisting of IHH and anosmia (KAL mutations) and hypogonadotropic hypogonadism associated with congenital adrenal hyperplasia (DAX-1 gene mutations), the etiology of IHH remains unknown. This project will attempt to identify affected individuals with IHH and to isolate candidate genes utilizing new approaches. The first specific aim will be to increase the number of IHH families in the database. The second aim will be to better characterize the phenotype of IHH patients based upon physical exam, endocrinologic studies, and pedigree structure. The third aim will be to use linkage analysis, linkage disequilibrium analysis, and association to identify candidate genes which might be involved in the pathogenesis of IHH. The identification of new genes is important for control of reproduction has tremendous implications for the treatment of pubertal disorders, infertility, and potentially contraception. Depending upon the types of mutations characterized, molecular diagnosis might be possible for children with delayed puberty. Female and male humans with idiopathic hypogonadotropic hypogonadism (IHH) typically present with delayed puberty, low serum gonadotropins, and the absence of pituitary dysfunction and tumor. Current endocrinologic evidence suggests that IHH is due to a deficiency of gonadotropin releasing hormone (GnRH), although heterogeneity exists in clinical, endocrinologic, and genetic attributes of the disorder. The hypogonadal mouse has hypogonadotropic hypogonadism due to a GnRH gene deletion, but no GnRH gene mutations have been identified in humans with IHH. Except for two X-linked disorders, Kallmann syndrome, consisting of IHH and anosmia (KAL gene mutations), and hypogonadotropic hypogonadism associated with congenital adrenal hypoplasia (DAX-1 gene mutations), the etiology of IHH remains unknown. The major goal of this proposal is to isolate genes important in the genesis of IHH. Our specific aims are: (1) To increase our number of IHH families; (2) to better characterize the phenotype of IHH patients based upon physical exam, endocrinologic studies, and pedigree structure; and (3) to use linkage, linkage disequilibrium, and association to test candidate genes which might be involved in the pathogenesis of IHH. Despite genetic heterogeneity, these genetic analyses provide important information for gene mapping. Although IHH is not a common disorder, it has certain important characteristics which make the understanding of its pathophysiology important since it affects puberty and reproduction in both sexes. The identification of new genes important in reproduction has tremendous implications for treatment of pubertal disorders, infertility, and potentially contraception. If a new gene is identified, a better understanding of IHH, and perhaps more importantly, normal reproduction, will be gained. Depending upon the types of mutations characterized, molecular diagnosis might be possible for children with delayed puberty. New therapies for the treatment of delayed puberty and infertility might also be possible once the protein structure and function are better understood. Potentially, contraceptive technologies could be developed based upon the understanding of the function of newly identified genes.